Bronchopulmonary dysplasia with focus on early prediction and treatment: a narrative review

Background and Objective: Bronchopulmonary dysplasia (BPD) remains a major cause of morbidity and mortality in very preterm infants though early non-invasive ventilation and surfactant treatment and other neonatal therapies have improved the outcome. Therefore, it is necessary to find effective supplemental methods for prediction of BPD. Better understanding of the etiology and molecular mechanisms involved in the pathogenesis of BPD is necessary for development of new effective early treatments. It is generally accepted that BPD is a multifactorial disease often associated with intrauterine infections and placental perfusion disorders. Methods: Recently a new method to predict BPD at birth using artificial intelligence (AI) has been developed. This new method improves the likelihood of developing effective early treatments for BPD. The method combines information on early surfactant treatment, birth weight and gestational age (GA) with analysis of the mid-infrared spectrum of the molecules in gastric aspirate which are produced in the newborn’s lungs. The described methods for early treatment of BPD in this review among others covers inositol, retinol, super oxide dismutase, Clara cell 10 protein, corticosteroids, azithromycin, macrolide and stem cell therapy besides general treatments as nasal continuous positive airway pressure (NCPAP), surfactant, caffeine, oxygen saturation targeting and nutrition. The literature search was performed systemically online via the databases PubMed and Medline between January 1, 2011 and December 31, 2022. Key Content and Findings: A method to predict BPD immediately after birth is now available allowing possibility to develop effective early treatments of BPD. Conclusions: The present review focuses on early prediction and the existing pharmacologic interventions highlighting the potential to improve the outcome of infants with BPD

Folding screening assayed by proteolysis: application to various cystine deletion mutants of vascular endothelial growth factor

The production of recombinant proteins in Escherichia coli often leads to the formation of inclusion bodies. Although this has a number of advantages, a major disadvantage is the need to develop folding protocols for the renaturing of the proteins. However, the systematic screening of folding conditions is often hampered by the lack of convenient assays to detect correctly folded proteins. To address this problem we present a simple protocol, which combines folding screens and limited proteolysis to rapidly assess and optimize folding conditions. The efficacy of this method, termed Fsap (folding screening assayed by proteolysis), is demonstrated by the large-scale folding, purification and crystallization of various cystine deletion mutants of the cystine knot family member: vascular endothelial growth factor (vegf). These mutants are particularly difficult to fold as the cystine knot is believed to make major contributions to the stability of the protein and this family of proteins lacks extensive hydrophobic core regions

Ligand recognition and homophilic interactions in Tyro3 - Structural insights into the Axl/Tyro3 receptor tyrosine kinase family

The receptor Tyro3 together with Axl and Mer form the Axl/Tyro3 family of receptor tyrosine kinases. Members of this family play essential roles in spermatogenesis, immunoregulation, and phagocytosis. Gas6, the product of growth arrest-specific gene, activates the kinase activity of all three receptors. Here, we report the first biochemical and structural characterization of a member of this family, namely of a fragment spanning the two N-terminal Ig domains of the extracellular part of human Tyro3. Its ligand binding specificity profile is identical to the activation profile of the native receptor. The 1.95-Angstrom crystal structure suggests a common ligand-binding site in this receptor family located at the interface of the Ig domains and unusually rich in cis-prolines. Furthermore, both in the crystal and in solution we observed the ligand-independent dimerization of the receptor fragment. This homophilic interaction emphasizes previous functional reports, which hinted that in addition to signal transduction, members of this family of receptors might participate in cell adhesion

The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor

Cystine knots consist of three intertwined disulfide bridges and are considered major determinants of protein stability in proteins in which they occur. We questioned this function and observed that removal of individual disulfide bridges in human vascular endothelial growth factor (VEGF) does not reduce its thermodynamic stability but reduces its unexpected high thermal stability of 108 °C by up to 40 °C. In wild-type VEGF ({delta}Gu,250 = 5.1 kcal·mol-1), the knot is responsible for a large entropic stabilization of T{delta}Su,250 = -39.3 kcal mol-1, which is compensated for by a {delta}Hu,250 of -34.2 kcal mol-1. In the disulfide-deficient mutants, this entropic stabilization disappears, but instead of a decrease, we observe an increase in the thermodynamic stability by about 2 kcal·mol-1. A detailed crystallographic analysis of the mutant structures suggests a role of the cystine knot motif in protein folding rather than in the stabilization of the folded state. When assuming that the sequential order of the disulfide bridge formation is conserved between VEGF and glycoprotein {alpha}-subunit, the crystal structure of the mutant C61A-C104A, which deviates by a root mean square deviation of more than 2.2 A from wild-type VEGF, identifies a true folding intermediate of VEGF

Effect of needle aspiration of pneumothorax on subsequent chest drain insertion in newborns: A randomized clinical trial

Importance: Treatment options for a symptomatic pneumothorax in newborns include needle aspiration (NA) and chest drain (CD) insertion. There is little consensus as to the preferred treatment, reflecting a lack of evidence from clinical trials. Objective: To investigate whether treating pneumothoraces diagnosed on chest radiography (CR) in newborns receiving respiratory support with NA results in fewer infants having CDs inserted within 6 hours of diagnosis. Design, Setting, and Participants: This randomized clinical trialwas conducted from October 7, 2013, to December 21, 2016. The setting was 5 tertiary European neonatal intensive care units. Infants receiving respiratory support (endotracheal ventilation, continuous positive airway pressure, or supplemental oxygen >40%) who had a pneumothorax on CR that clinicians deemed needed treatment were eligible for inclusion. Interventions: Infants were randomly assigned (1:1) to drainage using NA or CD insertion, stratified by center and gestation at birth (<32 vs 6532 weeks). Caregivers were not masked to group assignment. For NA, a needle was inserted between the ribs to aspirate air and was removed once air was no longer aspirated. A CD was inserted if clinicians deemed that the response was inadequate. For CD insertion, a drain was inserted between the ribs and was left in situ. Main Outcomes and Measures: The primary outcome was whether a CD was inserted on the side of the pneumothorax within 6 hours of diagnosis. Results: A total of 76 infants were randomly assigned, and 6 (4 assigned to NA and 2 to CD) were excluded because theymet exclusion criteria at enrollment. Of the 70 remaining infants, 33 (16 male [48%]) were assigned to NA and 37 (22 male [59%]) to CD insertion. Their median (interquartile range [IQR]) gestational age was 31 (27-38) vs 31 (27-35) weeks, and their median (IQR) birth weight was 1385 (1110-3365) vs 1690 (1060-2025) g, respectively. Fewer infants assigned to NA had a CD inserted within 6 hours (55%[18 of 33] vs 100% [37 of 37]; relative risk, 0.55; 95%CI, 0.40-0.75) and during hospitalization (70% [23 of 33] vs 100% [37 of 37]; relative risk, 0.70, 95%CI, 0.56-0.87). Conclusions and Relevance: Needle aspiration reduced the rate of CD insertion in symptomatic newborns with pneumothorax on CR. It should be used as the initial method of draining radiologically confirmed pneumothorax in symptomatic infants

European consensus recommendations for neonatal and paediatric retrievals of positive or suspected COVID-19 patients

BACKGROUND: The 2020 novel coronavirus (SARS-Cov-2) pandemic necessitates tailored recommendations addressing specific procedures for neonatal and paediatric transport of suspected or positive COVID-19 patients. The aim of this consensus statement is to define guidelines for safe clinical care for children needing inter-facility transport while making sure that the clinical teams involved are sufficiently protected from SARS-CoV-2. METHODS: A taskforce, composed of members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Transport section and the European Society for Paediatric Research (ESPR), reviewed the published literature and used a rapid, two-step modified Delphi process to formulate recommendations regarding safety and clinical management during transport of COVID-19 patients. RESULTS: The joint taskforce consisted of a panel of 12 experts who reached an agreement on a set of 17 recommendations specifying pertinent aspects on neonatal and paediatric COVID-19 patient transport. These included: case definition, personal protective equipment, airway management, equipment and strategies for invasive and non-invasive ventilation, special considerations for incubator and open stretcher transports, parents on transport and decontamination of transport vehicles. CONCLUSIONS: Our consensus recommendations aim to define current best-practice and should help guide transport teams dealing with infants and children with COVID-19 to work safely and effectively. IMPACT: We present European consensus recommendations on pertinent measures for transporting infants and children in times of the coronavirus (SARS-Cov-2 /COVID-19) pandemic. A panel of experts reviewed the evidence around transporting infants and children with proven or suspected COVID-19. Specific guidance on aspects of personal protective equipment, airway management and considerations for incubator and open stretcher transports is presented. Based on scant evidence, best-practice recommendations for neonatal and paediatric transport teams are presented, aiming for the protection of teams and patients. We highlight gaps in knowledge and areas of future research

Red Blood Cell Transfusion in European Neonatal Intensive Care Units, 2022 to 2023

International audienceIMPORTANCE Red blood cell (RBC) transfusions are frequently administered to preterm infants born before 32 weeks of gestation in the neonatal intensive care unit (NICU). Two randomized clinical trials (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants [ETTNO] and Transfusion of Prematures [TOP]) found that liberal RBC transfusion thresholds are nonsuperior to restrictive thresholds, but the extent to which these results have been integrated into clinical practice since publication in 2020 is unknown. OBJECTIVE To describe neonatal RBC transfusion practice in Europe. DESIGN, SETTING, AND PARTICIPANTS This international prospective observational cohort study collected data between September 1, 2022, and August 31, 2023, with a 6-week observation period per center, from 64 NICUs in 22 European countries. Participants included 1143 preterm infants born before 32 weeks of gestation. EXPOSURE Admission to the NICU. MAIN OUTCOMES AND MEASURES Study outcome measures included RBC transfusion prevalence rates, cumulative incidence, indications, pretransfusion hemoglobin (Hb) levels, volumes, and transfusion rates, Hb increment, and adverse effects of RBC transfusion. RESULTS A total of 1143 preterm infants were included (641 male [56.1%]; median gestational age at birth, 28 weeks plus 2 days [IQR, 26 weeks plus 2 days to 30 weeks plus 2 days]; median birth weight, 1030 [IQR, 780-1350] g), of whom 396 received 1 or more RBC transfusions, totaling 903 transfusions. Overall RBC transfusion prevalence rate during postnatal days 1 to 28 was 3.4 transfusion days per 100 admission days, with considerable variation across countries, only partly explained by patient mix. By day 28, 36.5% (95% CI, 31.6%-41.5%) of infants had received at least 1 transfusion. Most transfusions were given based on a defined Hb threshold (748 [82.8%]). Hemoglobin levels before transfusions indicated for threshold were below the restrictive thresholds set by ETTNO in 324 of 729 transfusions (44.4%) and TOP in 265 of 729 (36.4%). Conversely, they were between restrictive and liberal thresholds in 352 (48.3%) and 409 (56.1%) transfusions, respectively, and above liberal thresholds in 53 (7.3%) and 55 (7.5%) transfusions, respectively. Most transfusions given based on threshold had volumes of 15 mL/kg (470 of 738 [63.7%]) and were administered over 3 hours (400 of 738 [54.2%]), but there was substantial variation in dose and duration. CONCLUSIONS AND RELEVANCE In this cohort study of very preterm infants, most transfusions indicated for threshold were given for pretransfusion Hb levels above restrictive transfusion thresholds evaluated in recent trials. These results underline the need to optimize practices and for implementation research to support uptake of evidence